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Marijuana for the Treatment of Seizure Disorders

Emily Knezevich, PharmD, BCPS, CDE
Associate Professor of Pharmacy Practice
Creighton University School of Pharmacy & Health Professions

Omaha, Nebraska

Yunuo Wu, PharmD Candidate 2015
Creighton University School of Pharmacy & Health Professions
Omaha, Nebraska

US Pharm. 2015;40(1):24-28.

ABSTRACT: Cannabis, the substance more commonly known as marijuana, has gained interest in recent years for its potential use as an antiepileptic agent. The two main components of marijuana are delta-9-tetrahydrocannabinol, which has had mixed effects in epilepsy, and cannabidiol, which has shown more consistent anticonvulsant effects. Data supporting the use of marijuana for this purpose are limited, as the majority of clinical trials were conducted before 1990. There are case reports showing promising results; however, the data are inconsistent and cannot be generalized. The legal issues surrounding marijuana in the United States also may limit the use of this substance as an antiepileptic.

Epilepsy is defined as recurrent and ongoing seizures caused by changes in neuronal firing in the brain. Whereas nonepileptic seizures are not associated with neurophysiological changes, 3% of the population is predisposed to otherwise unprovoked, recurrent epileptic seizures. 1 Current pharmacotherapy for epilepsy aims to restore normal neuronal function and decrease seizure frequency. Prospective, randomized trials estimate that individuals experiencing a first, unprovoked seizure have a 40% to 50% chance of seizure recurrence at 2 years. The risk of recurrence, which diminishes with time, is highest immediately following the first seizure, with 80% to 90% of patients experiencing recurrent seizures within the first 2 years. 2,3 Despite available treatments, about 30% of patients remain resistant to therapy (fail two or more antiepileptics), resulting in poorly controlled and recurring seizures. 4,5 This review discusses the current research on, rationale for, and limitations to the use of marijuana for the treatment of seizure disorders.

Historical Medical Use of Cannabis

The earliest documented use of cannabis (marijuana) occurred in about 2,700 bc in China, where it was used for a variety of medical ailments, including gout, malaria, constipation, menstrual disorders, and absentmindedness. Western medicine adopted the use of cannabis as a common analgesic in the 19th century. 6

Cannabis was available in U.S. pharmacies as an OTC product until the 1937 Marihuana Tax Act limited its accessibility. Subsequently, the passing of the Controlled Substances Act in 1970 gave cannabis a Schedule I classification, making its use illegal. 7 Since 1970, there has been increasing interest in the use of marijuana for its possible antiepileptic properties. 4

Pharmacology

Cannabis sativa and Cannabis indica are two species of the Cannabis genus of flowering plants. Both of these species have a long history of use as an antiepileptic, with sativa strains causing more psychotropic and stimulating effects and indica strains causing more sedation. 6 Compounds contained in the cannabis plant are known as cannabinoids.

Cannabis contains two main components: the psychoactive portion of marijuana known as delta-9-tetrahydrocannabinol (THC) and the nonpsychoactive portion known as cannabidiol (CBD). What makes cannabis an attractive agent for epilepsy is the presence of cannabinoid type 1 receptors in the hippocampus and amygdala, both of which are associated with partial seizures. 8 The THC component of cannabis is a partial agonist at these receptors. 9 Conversely, CBD interacts with other nonendocannabinoid signaling systems, reducing the psychotropic activity of THC while increasing tolerance. 6 Recent trials of CBD have shown more consistent anticonvulsant properties, and this cannabinoid has gained interest as a possible agent for epilepsy. 9,10

There are many potential routes of administration for synthetic CBD, the only non–delta-9-THC phytocannabinoid assessed for its anticonvulsant effects in clinical trials. 6 The most common delivery route is by inhalation, either recreationally or for medicinal purposes. Because of the highly lipophilic nature of CBD and its high volume of distribution, the lungs are an effective route of medication delivery, with rapid distribution into the brain, adipose tissue, and organs. Cannabinoids are extensively metabolized by the liver, predominantly by CYP3A2, CYP3A4, CYP2C8, CYP2C9, and CYP2C19. Owing to significant first-pass metabolism through the liver, CBD is only about 6% bioavailable, thus rendering oral, oral-mucosal, and sublingual routes of delivery less desirable. The transdermal route of administration has also been considered; however, this route may be economically impractical, since special delivery systems are needed to prevent excessive accumulation of CBD in the skin. 11,12

Marijuana as Treatment

Clinical trials examining the efficacy of marijuana for treating epilepsy are limited. One of the earliest was a small randomized, controlled study conducted by Mechoulam in 1970. 13 In this trial, nine patients with treatment-resistant temporal lobe epilepsy received either CBD or placebo for 5 weeks in addition to their current antiepileptic therapy. Two of the four CBD patients were seizure-free at 3-month follow-up, whereas none of the five placebo patients showed improvement. However, this trial was limited by its small sample size and lack of statistical analysis or power calculation. 13

Cunha and colleagues conducted a small randomized, controlled trial involving 15 patients with generalized epilepsy. 14 Seven patients received CBD and eight received matching placebo for 3 to 18 weeks. There were no reported toxicities, and four CBD patients compared with just one placebo patient were seizure-free. This study was limited in that it had no performed power calculation, no statistical analysis, and a small sample size. 14

Although a number of early small, controlled studies demonstrated some efficacy of CBD for epilepsy, more recent studies indicate that CBD has limited or no effect on epilepsy. In one trial, Trembly and Sherman examined the effect of marijuana on uncontrolled epilepsy. 15 No discernible effect was found overall, and there was no statistical analysis of trial outcomes or main effects. A study conducted by Ames and Cridland showed no difference between CBD and placebo. 16 As was the case in previous trials, the study population was small and there were no power calculations. 16

Various case reports have identified adult patients favoring marijuana as antiepileptic treatment, as well as parents who have sought marijuana with CBD content to treat resistant epilepsy in their children. 7,17,18 Some of these reports yield promising information; however, there is no consensus on dosage, formulation, route of administration, or duration of marijuana therapy. Placebo effect and recall bias may be confounding variables. These limited case reports highlight that there is a paucity of safety and efficacy data from randomized, controlled trials to establish the use of marijuana for the treatment of epilepsy. See TABLE 1 for a summary of studies on cannabinoid use as an antiepileptic.

Adverse Effects

Adverse effects of chronic marijuana use include addiction risk, negative effects on brain development, increased risk of certain mental illnesses, motor-vehicle accidents, and various effects on health. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 9% of individuals who use marijuana may become addicted. In addition, discontinuation of habitual cannabis use may cause withdrawal symptoms such as irritability, insomnia, dysphoria, enhanced cravings, and increased anxiety. 19

Marijuana initiation at a young age may impact brain development, as it can impair neural connectivity in specific areas of the brain, resulting in altered learning, memory, and function. Marijuana use in adolescence could lead to a heightened response to other drugs, paving the way for addictions to other drugs in adulthood.

Consistent marijuana use has been correlated with anxiety and depression; however, a causal relationship has not been established. There may also be a positive association between chronic marijuana smoking and an increased incidence of lung cancer, as well as other pulmonary diseases, through lung airway inflammation, airway resistance, and hyperinflation. 8,19

Heavy and chronic marijuana use may be correlated with the majority of the adverse effects, mostly attributable to the THC component. However, there may also be confounding variables; therefore, causality cannot be established. Future studies involving CBD may result in a different side-effect profile, since multiple small studies of CBD safety in humans have shown adequate tolerance with no significant side effects at dosages up to 1,500 mg per day by mouth or 30 mg IV when used acutely and chronically. 6,20

Current Medical Use

Currently, the FDA has not approved marijuana for any indication. However, 23 states and Washington, DC, have legalized the use of medical marijuana (containing delta-9-THC), and 22 states have approved it for seizure use (TABLE 2). In addition, Massachusetts allows marijuana for “conditions as determined in writing by a qualifying patient’s physician.” 21 Medical marijuana use is licensed in Canada, the Netherlands, and Israel. 9

Future research involving drug products derived from botanical marijuana or synthetic versions and substances that act similarly to marijuana must be approved via an Investigational New Drug Application before human trials can be conducted. In addition, the Drug Enforcement Administration reviews the researcher registration application, and the National Institute of Drug Abuse is responsible for supplying research marijuana for trials. Ultimately, for a drug product to be approved for the U.S. market, the FDA must ensure that it meets necessary quality standards and is safe and efficacious. 22

Conclusion

There is insufficient evidence to form a reliable conclusion regarding the efficacy of marijuana as an antiepileptic agent. Despite case reports demonstrating efficacy in reducing seizure frequency and severity, limited clinical studies have been published on its use for this indication. Additionally, the studies conducted were inadequately powered, lacked complete information, and used small sample sizes. There are few studies of long-term administration of cannabis and its safety profile. Currently, legal restrictions on cannabis make it difficult to conduct large-scale clinical trials, as the FDA has classified marijuana as a Schedule I controlled substance. The utility of marijuana for the therapeutic treatment of epilepsy cannot be determined at this time; more large-scale studies are needed that assess the efficacy and safety of treatment with either high CBD-THC ratio marijuana or isolated CBD compounds.

Marijuana for the Treatment of Seizure Disorders Emily Knezevich, PharmD, BCPS, CDE Associate Professor of Pharmacy Practice Creighton University School of Pharmacy & Health Professions

Best Cannabis Strains for Seizures + Epilepsy

The use of marijuana in the treatment of seizures and epilepsy is a widely discussed topic. Seizures are classified as unusual electrical activity in the brain that can manifest in a variety of ways, including the shaking of all or part of the body, a change in behavior, or a change in consciousness level. Seizures are a symptom of epilepsy. However, not all people with seizures necessarily have epilepsy. There are also types of seizures called psychogenic nonepileptic seizures. These may be the result of a psychiatric disorder (and not a physical cause).

In 2018, the United States Food and Drug Administration approved a medication comprised of CBD for the treatment of seizures associated with two specific types of epilepsy. The medication is called Epidiolex, and it can be used in patients who have Lennox-Gastaut syndrome and Dravet syndrome. Studies showed that taking Epidiolex in combination with other medications could reduce the frequency that these patients experience seizures.

Given the efficacy of Epidiolex and of Charlotte’s Web (whose story is outlined below), it is possible that other forms of CBD may also play a role in treating seizures. Here are five strains of cannabis that may be beneficial. Please note that these haven’t been proven to be the best strains for seizures and epilepsy in any studies; they are merely our recommendations based on their CBD content.

1. Charlotte’s Web

This is one of the most popular strains suggested to help with seizures. It is named after Charlotte Figi, a little girl who suffered from Dravet Syndrome, a rare form of epilepsy (and one of the forms that can be treated with Epidiolex). The Stanley Brothers developed Charlotte’s Web to help with Charlotte’s rare condition. It contains an average of 0.3% THC and very high amounts of CBD. As a result, this strain may be ideal for epilepsy patients who don’t want the risk of intoxication.

The Stanleys were able to significantly reduce the THC content of the strain while still boosting its CBD. They created a product with an exceptionally calming “body high” without any mental side effects. Little Charlotte was experiencing extremely violent seizures hundreds of times a week before she used CBD. After she started using the high-CBD cannabis oil, her seizures were reduced from over a thousand to just a handful each month. This strain has a “web-like” appearance, with thick, long trichomes wrapped around the buds.

Charlotte’s Web is still a relatively rare strain. Nonetheless, it is highly sought after by medical marijuana communities across the country, as many proponents claim that Charlotte’s Web is hugely effective in reducing seizures.

2. ACDC

The ACDC strain is an evenly-balanced hybrid with a 50:50 sativa to indica ratio. The reason that this strain makes this list is that it is a high CBD, low THC strain. Some ACDC strains can contain up to twenty times more CBD than THC. More typically, though, the ACDC strain contains, on average, approximately 6% THC and around 15% CBD. Therefore, this strain more commonly has a CBD: THC ratio of about 2.5:1.

Another potential benefit of this strain is because of its low THC content; consumers are unlikely to experience a psychoactive high after using it. Many users of this strain describe its effects as predominantly uplifting and relaxing. Due to its well-balanced genetics, consumers of the ACDC strain are unlikely to experience any drowsiness or sedating effects. This makes the ACDC strain suitable for daytime use.

3. Cannatonic

Cannatonic is potentially useful for managing epilepsy and seizures, headaches, fatigue, muscle spasms, migraines, and chronic pain. It offers a less-cloudy, focus-inducing high because of its low THC content, which is between 7% and 15%. It also has a high CBD content of approximately 12%.

A powerful and relaxing strain, Cannatonic could help to focus the mind. However, these effects are overshadowed by the intense numbing and warming sensations that flow over the body. Cannatonic is unique in its chemical composition, which doesn’t have the sole purpose of getting the user high. Instead, it could work on medical conditions from the inside out.

This strain has the potential to profoundly enhance mood, as some say it seems as if they are floating on a cloud after consuming it. Possible outcomes include increased feelings of positivity and optimism, together with a boost of energy. Users say the high is calm, and the strain is suitable for use at any time of the day. Cannatonic shouldn’t seriously affect motivation levels or produce any drowsiness or sleepiness.

4. Ringo’s Gift

While reports of the THC contained in Ringo’s Gift tend to vary considerably, many believe that this strain has an extremely low THC content and a significantly higher CBD content. Some suggest that Ringo’s Gift contains as little as 1% THC and around 15% CBD.

Ringo’s Gift is named after Lawerence Ringo, who was a cannabis activist and an advocate of the potential benefits of high CBD strains. Many consumers of this strain say that it can deeply relax the body without causing couch-lock or any feeling of sedation. This makes Ringo’s Gift a potential daytime option for cannabis consumers.

5. Harlequin

Harlequin is the only sativa-dominant (75:25) hybrid on this list. As is the case with the ACDC and Cannatonic strains, Harlequin contains a higher CBD than THC content. Most Harlequin strains contain an average THC range of between 7-10% and a CBD level of between 8.5-15%.

Many Harlequin consumers describe its effects as uplifting and mildly energizing, to begin with. These initial effects tend to taper off before being replaced by a feeling of relaxation.

Harlequin consumers say that its cerebral effects are relatively clear-headed, which allows them to continue to carry on with their daily tasks. This makes the Harlequin strain suitable for daytime consumption.

Final Thoughts on Cannabis Strains for Seizures and Epilepsy

On June 25, 2018, the Food and Drug Administration approved a medication called Epidiolex, which is now used to treat two specific kinds of childhood epilepsy, namely Lennox-Gastaut Syndrome and Dravet Syndrome. As the active ingredient in Epidiolex is CBD, this has naturally piqued the interest of cannabis consumers who have epilepsy.

However, we would caution anyone considering consuming any of the strains on this list, or any other high-CBD strain for that matter, to discuss it with their medical professional before doing so.

We are not medical experts at WayofLeaf, and none of the information contained in this article is meant in any way, shape, or form, to be interpreted as us giving medical advice to our readers. As mentioned above, the strains that appear on this list were merely chosen as they contain significant amounts of CBD, and cannabidiol is one of the main ingredients used in Epidiolex.

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